Towards an Understanding of Integrative Brain Functions

Signal transduction of molecules at the glutamatergic
postsynaptic membrane

Abstract
We have applied techniques from modern
molecular biology and biochemistry to unravel the complex
molecular structure of the postsynaptic membrane at glutamargic
synapses in the central nervous system. We have characterized a
set of new proteins that are constituents of the postsynaptic
density, including PSD-95, densin-180, citron (a rho/rac effector
protein), and synaptic gp130 Ras GAP (a new Ras GTPase-activating
protein). The structure of PSD-95 revealed a new protein motif,
the PDZ domain, that plays an important role in the assembly of
signal transduction complexes at intercellular junctions. More
recently, we have used new imaging tools to observe the dynamics
of authophosphorylation of CaM kinase II in intact hoppocampal
tissue. We have been able to detect changes in the amount of
autophosphorylated CaM kinase II in dendrites, individual synapses,
and somas of hippocampal neurons following induction of long-term
potentiation by tetanic stimulation. In addition, we have
observed a specific increase in the concentration of CaM kinase
II in dendrites of neurons receiving tetanic stimulation. This
increase appears to be the result of dendritic synthesis of new
protein. Over the next several years we will apply similar
methods to study regulatory changes that occur at the molecular
level in glutamatergic synapses in the CNS as the brain processes
and stores new information.